RU2665959C1 - Spray for emergency prevention of acute respiratory viral infections - Google Patents

Abstract

FIELD: pharmaceuticals.SUBSTANCE: invention relates to the pharmaceutical industry and is a spray for the emergency prevention of acute respiratory viral infections, containing water, characterized in that it contains sodium chloride and sodium hypochlorite solution with pH equal to 8.0–10.0, an active chlorine concentration of 0.30–0.60 mg/l and a droplet size of 90–110 mcm, the spray components are in a certain ratio, in wt. %.EFFECT: invention provides increased effectiveness of ARVI prophylaxis, expressed in preventing the disease during epidemics, reduced severity of the disease, reduced number of complications in patients who are provided with the virucidal action of the proposed drug, the ability to increase local immunity of mucous membranes, the ability to activate oxidative processes in tissues.1 cl, 4 ex

Description

The invention relates to medicine and can be used for the manufacture of tools for emergency prevention of acute respiratory viral infections (ARVI).

Emergency prophylaxis refers to measures aimed at preventing the diseases of persons who have been in contact with patients in the event of their possible infection.

ARVI - polyetiological diseases. Currently, more than 200 SARS pathogens are known, but rhinoviruses (30-50%) and influenza viruses (5-15%), causing a high flare incidence in the autumn-winter period, are predominant, adenoviruses, parainfluenza viruses, and respiratory infections are much less common. syncytial virus. Prevention of such a disease of acute respiratory viral infections, including and influenza involves either increasing the patient’s immune status through pre-vaccination before the onset of the epidemic or the introduction of drugs with immunomodulating properties. A common drawback for all influenza vaccines is the obligatory matching of the strain from which the vaccine is made, which often leads to complete inefficiency of vaccination. In these cases, drugs that destroy viruses, for example, remantadine (methyl-1-adamantyl-methylamine hydrochloride), are used. However, the maximum virus-inhibiting activity of rimantadine is manifested only in relation to serotypes of type A virus, to a lesser extent in relation to type B influenza virus, as well as other respiratory viruses. In addition, with the use of rimantadine, sensory organs disorders (sensation of tinnitus), digestive system disorders (stool disorders, stomach pain, abdominal pain, nausea, vomiting, increased bilirubin level, dry mouth, decreased appetite are possible ), disorders of the respiratory system, allergic reactions.

As prophylactic agents for the prevention of acute respiratory viral infections, interferon preparations (Amiksin, Kagocel) and interferon formation inducers (Grippferon) are used. A common drawback of interferon inducers is the duration of the drug for the manifestation of this therapeutic effect, and the disadvantage of Grippferon is that it can cause pathological forms of blood cells; insomnia, breakdown, dizziness; palpitations; skin rashes; stool problems sore throat, cough.

For the treatment and prevention of influenza and other acute respiratory viral infections, several groups of antiviral drugs are recommended, among which, for example, the ion channel locator (Rimantadine), which was used until recently for the treatment and prevention of influenza A 6. However, at present, Rimantadine is not recommended to be prescribed, because the vast majority of circulating strains of influenza viruses are resistant to it, and it does not act on the causative agents of other acute respiratory viral infections.

There is evidence of the use of neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) as effective agents for treating influenza (including pandemic) when prescribed no later than 24-48 hours from the onset of clinical symptoms of the disease (1).

However, these drugs have serious side effects, which requires mandatory medical participation. For example, a Relenza inhaler can cause shortness of breath and bronchospasm. Drugs can also cause allergic reactions in the form of edema. In connection with the above, there is a high need for the development of a safe, easy-to-use, and not causing serious complications, tool for emergency non-specific prevention of acute respiratory viral infections.

In the Russian Federation, various sprays have been registered for the treatment of infections of the upper respiratory tract, including viral origin: Hexoral, Miramistin, Tantum Verde. However, the instructions for none of these drugs do not indicate the possibility of using them for the prevention of acute respiratory viral infections (2).

As the only prophylactic in ARVI with an official indication of this use, the Aquamaris spray was identified in the instructions for use of the drug (1). Its action is the mechanical removal of SARS viruses from the mucous membranes of the nose and oropharynx, which prevents the attachment and further replication of viruses. There is evidence of a positive effect of Aquamaris on local mucosal immunity. However, this tool cannot have an effective effect on preventing the penetration of ARVI viruses into the cells of the mucous membranes, since it does not have virucidal activity and does not alter the local immunity of the nose and oropharynx.

The specified drug Aquamaris is selected by us as a prototype means according to the claimed invention.

As a means of preventing acute respiratory viral infections, which has a higher prophylactic effect, we propose a spray of sodium hypochlorite solution.

It is known that sodium hypochlorite under natural conditions in the human body is produced by macrophages in the process of bacterial phagocytosis and is a substance with almost universal detoxifying, antimicrobial and antiviral properties. Being a donor of active oxygen and a powerful oxidizing agent, sodium hypochlorite in the body breaks down into the hypochlorite anion (ClO) and sodium ion (Na ⁺ ). Hypochlorite anion reacts with a huge number of substrates found in biological fluids, on and inside cell membranes. As a result of oxidation or chlorination of these substrates, the polydirectional effect of sodium hypochlorite on the organs and systems of the patient's body is manifested.

We have not found fame for the use of sodium hypochlorite solutions for the prevention of acute respiratory viral infections. Available in the literature information on the bactericidal and antiviral effects of this agent relate to the treatment of bacterial infections and the disinfecting properties of sodium hypochlorite solutions. The use of sodium hypochlorite in dentistry and otorhinolaryngology has shown the safety and effectiveness of applying weak hypochlorite solutions to the mucous membranes of the oropharynx and nose for the treatment of bacterial infections (3, 4).

The technical result of the invention is to increase the effectiveness of prevention of acute respiratory viral infections, expressed in the prevention of disease during epidemics in a large number of people, as well as reducing the severity of the disease, reducing the number of complications in patients due to the virucidal effect of the proposed drug, the ability to increase local immunity of the mucous membranes, the ability to activate oxidative processes in the tissues.

This technical result is achieved by the fact that in the known spray for emergency prevention of acute respiratory viral infections, as a liquid phase, the spray contains a solution of sodium hypochlorite with a pH of 8.0-10.0, an active chlorine concentration of 0.30-0.60 mg / l and a droplet size of 90-110 μm with the following ingredients in wt.%:

Sodium hypochlorite 0,030-0,060 Sodium chloride 0.8-1.0 Water The rest is up to 100.0

An aqueous solution of sodium hypochlorite with specified parameters was obtained by the electrochemical method, i.e. by electrolysis of an aqueous solution of sodium chloride on the apparatus DEO-01-MEDEC. Sodium hypochlorite was obtained by the electrochemical method described in book. V.L. Kubasov, V.V. Bashmakov. Electrochemical technology of inorganic substances. M .: Chemistry, 1989, p. 136.

As indicated in the manuals for the apparatus for the electrolysis of verified salt, the ratio of the ingredients obtained, i.e. sodium hypochlorite and sodium chloride depends on the strength, current density, type of electrodes and the initial concentration of sodium chloride solution. In the process of electrolysis, samples were taken and sodium hypochlorite solution was analyzed for the content of active chlorine, sodium chloride and pH.

Quantification of sodium hypochlorite

The amount of sodium hypochlorite was determined by the amount of active choir according to the method described in GOST 11086-76 “Sodium hypochlorite”.

The mass content of sodium hypochlorite X, wt. % is calculated by the formula:

X = (0.003723 × 250 × 10000 × V) / (10 × 10 × 100),

wherein V, cm ³ - volume sodium concentration sernovatistokislogo exactly 0.1 mol / dm ^3, consumed for the titration.

0,003723 - the mass of sodium hypochlorite, corresponding to 1 cm of a solution of sodium sulfate, concentration exactly 0.1 mol / DM ³ .

Determination of sodium chloride was carried out according to the method of Mohr using silver nitrate (AgNO ₃ ) and potassium chromate (K ₂ CrO ₄ ).

After chemical analysis of the resulting solution and if it meets the requirements, this solution is placed in a spray container, the design of which made it possible to obtain a spray with a predominant droplet size of 90-110 microns.

The impact on the upper respiratory tract with sodium hypochlorite solution in the form of a spray was carried out as follows.

The spray was applied 2 times a day: in the morning (before contacts with other possible ARVI carriers) and in the evening at 17-20 hours (after contacts). The spray dispenser was designed for 0.5 ml of solution. Before spraying, it was necessary to remove the cap from the bottle and put on the metering valve, which had to be pressed twice so that the product was delivered to the dispenser head. It was necessary to irrigate the tonsils with a lowered tongue, so that all affected tissues and lacunae were processed. For this, the inhaler had to be administered as close to the tonsils as possible. The bottle had to be held upright. Before injection, you should hold your breath and press the spray valve sharply, twice, directing the nozzle of the dispenser in different directions. It was recommended to refrain from swallowing saliva for about 3 minutes. The nasal cavity was treated by spraying the solution into the nasal passages. When tonsils were irrigated, 1-3 valve pressures were performed, i.e. 0.5-1.5 ml of sodium hypochlorite solution was injected, and with irrigation of the nose, one pressing for each nasal passage is sufficient.

Examples of preparation

Example No. 1

By electrolysis of a 0.9% aqueous solution of sodium chloride having a pH of 7.4 (after alkalization) on a DEO-01-MEDEC apparatus at a current strength of 3A for 6 minutes, a sodium hypochlorite solution with a sodium hypochlorite concentration of 0.030% in 0.9% was obtained sodium chloride solution.

The pH of the resulting solution was 8.0.

The solution was placed in a spray container made of opaque plastic.

Example No. 2

By electrolysis of a 0.9% aqueous solution of sodium chloride with a pH of 7.9 (after alkalization) on a DEO-01-MEDEC apparatus at a current of 5A for 6 minutes, a sodium hypochlorite solution with a concentration of sodium hypochlorite of 0.06% in 0.9 was obtained % solution of sodium chloride.

The pH of the solution was 8.5. By adding caustic soda, the pH was increased to 9.0.

The solution was placed in a spray container.

Example No. 3

By electrolysis of a 0.9% aqueous solution of sodium chloride with a pH of 7.9 (after alkalization) on a DEO-01-MEDEC apparatus at a current of 5A for 6 minutes, a sodium hypochlorite solution with a concentration of sodium hypochlorite of 0.06% in a sodium chloride solution was obtained .

The pH of the solution was 8.5. By adding caustic soda, the pH was increased to 10.0

The solution was placed in a spray container.

Example No. 4

By electrolysis of a 0.9% aqueous solution of sodium chloride with a pH of 7.6 (after alkalization) on a DEO-01-MEDEK apparatus at a current of 5 A for 6 minutes, a solution of sodium hypochlorite with a concentration of sodium hypochlorite of 0.060% in a solution of sodium chloride was obtained.

The pH of the solution was 8.0.

The solution was placed in a spray container.

Justification of some parameters of the proposed tool

The size of the droplets of the spray 90-110 microns due to the following.

Drop sizes 90-110 μm 0.03% -0.06% sodium hypochlorite solution in a larger amount fall into the crypts and are adsorbed by the mucosa. This was confirmed by the results of a quantitative determination of sodium hypochlorite in swabs from the nasopharynx. To do this, the subjects after processing the nasopharynx with sodium hypochlorite spray three times gargled with a sterile saline solution of 10-15 ml of liquid. Washings were collected in a wide-necked sterile jar, after which the amount of sodium hypochlorite was determined in the collected liquid according to the method described in GOST 11086-76 “Sodium hypochlorite”. It was found that the amount of sodium hypochlorite adsorbed on the mucosa is greatest when the droplet size is 90-110 microns. This is apparently caused by the following. As we have revealed in a series of typical experiments, drops of a solution of less than 90 microns penetrate the trachea and bronchi, and drops larger than 110 microns after application to the mucous membranes merge with each other and flow into the esophagus.

The pH of the product is 8.0 to 10.0 due to the following.

In the acidic and neutral environment of sodium hypochlorite solutions, the proportion of hypochlorous acid, HCl, is 78%, and hypochlorite - 22%, in an alkaline environment, even at pH = 8, the proportion of hypochlorous acid, HCl, only 24%, hypochlorite - 76%. However, the stability of hypochlorite solutions increases with increasing pH. Aqueous solutions of sodium hypochlorite are very unstable and decompose over time even at ordinary temperatures (at a rate of 0.08 to 0.1% per day). The decay rate of sodium hypochlorite is affected by exposure to solar radiation, the presence of heavy metal cations and alkali metal chlorides. It should be noted that solutions with a strongly alkaline medium (pH> 10) are most stable (5).

When stored at room temperature in spray containers of 0.057-0.06% sodium hypochlorite solutions at pH 9-10.0, it was found that after 1 month the concentration of sodium hypochlorite decreases by 5-7%, and at pH 8-8, 5, this concentration is reduced by 7-8%.

The concentration of sodium hypochlorite in a solution of 0.03-0.06% was chosen after a study on the prevention and treatment of acute respiratory viral infections, according to which the indicated concentration gave the best results.

The tool was tested on 200 volunteers (students of one university, age 19-22, 70 of whom used a hypochlorite spray with a concentration of 0.03% (group 1), 70 people used a sodium hypochorite spray with a concentration of 0.06% (group 2), and 60 people made up the control group (group 3), which was sprayed with an isotonic sodium chloride solution in the form of a spray.The impact on the upper respiratory tract with sodium hypochlorite solution in the form of a spray was carried out as follows.

The spray was applied 2 times a day: in the morning (before contacts with other possible ARVI carriers) and in the evening at 17-20 hours (after contacts). The spray dispenser was designed for 0.5 ml of solution. Before spraying, it was necessary to remove the cap from the bottle and put on the metering valve, which had to be pressed twice so that the product was delivered to the dispenser head. It was necessary to irrigate the tonsils with a lowered tongue, so that all affected tissues and lacunae were processed. For this, the inhaler had to be administered as close to the tonsils as possible. The bottle had to be held upright. Before injection, you should hold your breath and press the spray valve sharply, twice, directing the nozzle of the dispenser in different directions. It was recommended to refrain from swallowing saliva for about 3 minutes. The nasal cavity was treated by spraying the solution into the nasal passages. When tonsils were irrigated, 1-3 valve pressures were performed, i.e. use 0.5-1.5 ml of sodium hypochlorite solution, and with irrigation of the nasal cavity, one press was enough for each nasal passage. Prevention was carried out for 20 days. Moreover, irrigation continued with the test subjects, against the background of the traditional treatment of acute respiratory viral infections.

We studied the severity of the clinical course of the infectious process in patients, the condition of the mucous membranes of the oropharynx and tonsils.

The immune status was characterized by the following methods:

1. The generally accepted hematological methods determined the total content of leukocytes, as well as the relative and absolute number of lymphocytes in the peripheral blood.

2. Determined secretory immunoglobulin A (SIgA) saliva. Saliva was taken in the morning on an empty stomach in a test tube cooled to 40 ° C. In the obtained samples, the content of secretory IgA was evaluated by ELISA kits “Vector-Best”, Novosibirsk. Salivary immunoglobulin A (SIgA) is a primary response factor in the body’s immune system, which plays an important role in protecting the body against respiratory viruses in the local oropharynx local immunity system. It binds foreign agents directly at the place of their introduction - on the mucous membranes of the oral cavity, respiratory tract and digestive tract and does not allow them to penetrate the internal organs (lungs, heart, liver) (6,7)

3. In patients (as a rule, the disease arose on the 7-10th day of the experiment), the type of virus was determined by immunofluorescence analysis (IMP) of the hemagglutination inhibition reaction (RTGA) and the compliment binding reaction (CSC). A 4-fold increase in antibody titer was of diagnostic value.

The protective effect of sodium hypochlorite was evaluated by the incidence of influenza and other acute respiratory viral infections, the severity of the disease and the studied indicators of immune status in the experimental and control groups.

Of the persons of the first group (70 people) using a spray with a concentration of sodium hypochlorite of 0.03%, 20 people fell ill for 20 days (on days 2-4 of the experiment), which is 11%, in the 2nd group using a spray with a concentration of sodium hypochlorite 0.06%, 4 people were ill or 5.7%, in the control group (60 people, group 3) there were 20 people (on 10-20 days of the experiment), which is 33%. Thus, the use of a spray of sodium hypochlorite solution at a concentration of 0.03% ensured a decrease in the incidence of acute respiratory viral infections by 3 times, at a concentration of 0.06% by almost 6 times.

Sick 2 people in the 1st experimental group, 1 person in the 2nd experimental group and 3 people in the control group had a parainfluenza clinic. Moreover, in the control group, the severity of the disease was more pronounced. The clinical picture was dominated by signs of damage to the upper respiratory tract, pain and sore throat, nasal congestion, dry cough, and symptoms of rhinopharyngitis. The clinical diagnosis was confirmed by the IMP method, which showed the presence of HPIV 1 parainfluenza viruses in epithelial cells of the nasal mucosa.

Using rtga and ccs, paired blood serum was studied, taken at intervals of 10-14 days from the onset of the disease. An increase in the titer of antibodies to the virus type HPIV 1 confirmed this diagnosis.

Sick 5 people in 1-2 experimental groups and 13 people in the control group had a clinic of adenovirus infection. The disease in patients of the control group began acutely with an increase in body temperature, a headache, weakness, decreased appetite, and muscle pain. Patients had nasal congestion and a runny nose, rhinopharyngitis and rhinopharyngotonzillitis. Conjunctivitis was diagnosed in 3 patients of the control group, and diarrhea in 5. Objectively: an increase in peripheral lymph nodes. In the peripheral blood of 6 patients, normocytosis, in 4 leukopenia, ESR is not increased. The duration of the disease averaged 14-20 days. In 4 people in the experimental groups with laboratory-confirmed adenovirus infection, body temperature was within 37.5 ° C, the disease was limited to rhinopharyngitis without conjunctivitis. The duration of the disease was 7-10 days. In 3, the duration of the disease was 11-14 days with severe rhinopharyngotonzillitis. IFL, RSK and RTGA showed the presence in the body of patients with serological types of adenoviruses 3.4 and 7. The duration of the disease in groups 1-2 was on average 10-12 days against a background of low temperature, while in no case was the development of pneumonia, conjunctivitis diarrhea.

4 people in the experimental 1-2 groups and 4 people in the control group at the clinic were assigned to the sick flu.

The disease began acutely, sometimes with chills. The temperature rose rapidly, reaching already in the first day 38-39 ° C. Signs of general intoxication (weakness, adynamia, sweating, headache, lacrimation) and symptoms of respiratory tract damage (dry cough, sore throat, hoarseness, nasal congestion) were noted. During the examination, hyperemia of the face and neck, vascular injection of the sclera, increased sweating, bradycardia, hypotension were noted. A diffuse lesion of the upper respiratory tract (rhinitis, pharyngitis, laryngitis, tracheitis) was detected. Hyperemia and a peculiar granularity of the mucous membrane of the pharynx were characteristic, in the peripheral blood - leukopenia, neutropenia, ESR is usually not increased.

Subsequently, 3 patients from the control group against the background of specific anti-influenza treatment had complications in the form of pneumonia. In patients of the experimental group who received similar treatment, no complications were noted.

The diagnosis of influenza was confirmed by the method of IMP, RTGA and CSC. In 7 cases, the influenza virus of the subtype A (H ₁ N ₁ ) was the cause of the development of influenza, and type B virus in 1 patient.

The above indicates that the persons of both the experimental and control groups were in contact with patients with influenza, parainfluenza and adenovirus infection.

. В процессе эксперимента в опытных группах отмечено достоверное возрастание этого показателя до

на 7 день, и до

на 20 день. В контрольной группе изменения количества A (SIgA) слюны не отмечалось.Prior to the experiment, as well as on the 7th, 14th and 20th day of the experiment, salivary immunoglobulin A (SIgA) was determined for all participants. Its initial value averaged

. During the experiment in the experimental groups, a significant increase in this indicator to

on day 7, and before

on day 20. In the control group, there was no change in the amount of A (SIgA) saliva.

Thus, the presented results indicate a reliable prophylactic effect of the spray of sodium hypochlorite solution against viruses of type A, B, as well as against parainfluenza viruses and adenoviruses. The preventive and therapeutic effect of the proposed drug is also manifested in a milder course of ARVI disease, as well as a decrease in the number of complications in people using the spray.

The effect of sodium hypochlorite solution is caused not only by its known virucidal properties, but also by the ability to increase local immunity of the mucous membranes of the oropharynx, which is expressed in an increase in the amount of A (SIgA) saliva. Apparently, this previously unknown effect is the result of the antioxidant properties of sodium hypochlorite.

Literature

1. G.N. Karetkina “Influenza and SARS: Treatment and Prevention in the Coming Epidemic Season 2015-2016, Journal of the CURING DOCTOR November 2015, No. 11.

2. The state register of medicines. http://www.grls.rosminzdrav.ru.

3. Suleymanov Yu.B. Abstract and dissertation: "Local and systemic use of sodium hypochlorite in the treatment of acute maxillary sinusitis", Moscow 2004

4. Perova M.D. and others. "Sodium hypochlorite and its use in dentistry" g. Dentistry - 1989. - No. 2., P. 84-87.

5. http://wwtec.ru/index.php?id=410.

6. Leonova M.V., Efremenkova O.V. Local immunomodulation in diseases of the upper respiratory tract. // Good practice. - 2002. - No. 1. - S. 14-22.

7. Wines B.D., Hogarth P.M. IgA receptors in health and disease. Tissue Antigens. - 2006. - Vol. 68, No. 2. - P. 103-114.

Claims (2)

Spray for emergency prevention of acute respiratory viral infections, containing water, characterized in that it contains sodium chloride and sodium hypochlorite solution with a pH of 8.0-10.0, an active chlorine concentration of 0.30-0.60 mg / L and size drops of 90-110 microns, with the following ingredients, wt.%: Sodium hypochlorite 0,030-0,060 Sodium chloride 0.8-1.0 Water The rest is up to 100.0